CN117159568A - Application of dicaffeoyl glucose in preparation of medicines for treating and/or preventing and/or relieving and/or improving parkinsonism - Google Patents
Application of dicaffeoyl glucose in preparation of medicines for treating and/or preventing and/or relieving and/or improving parkinsonism Download PDFInfo
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- 208000027089 Parkinsonian disease Diseases 0.000 title claims abstract description 20
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- 238000002360 preparation method Methods 0.000 title claims description 7
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- 239000008103 glucose Substances 0.000 title abstract description 25
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- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 20
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The application discloses application of dicaffeoyl glucose. The application is an application in the following: (1) Preparing a medicament for treating and/or preventing and/or relieving and/or improving parkinsonism; (2) Preparing a medicament for treating and/or preventing and/or relieving and/or improving the symptoms of an animal model of the parkinsonism. Experiments prove that the dicaffeoyl glucose can treat the Parkinson disease of the zebra fish.
Description
Technical Field
The application belongs to the field of medicines, and particularly relates to application of dicaffeoyl glucose in preparation of medicines for treating and/or preventing and/or relieving and/or improving parkinsonism.
Background
Parkinson's disease (pd) is a common central nervous system degenerative disease of the elderly population, mainly causing movement disorders such as resting tremor, myotonia, bradykinesia and abnormal posture gait, accompanied by a large number of non-motor symptoms. The prevalence rate of parkinson's disease, the incidence rate increases by a factor of two with age, and in 2016, 610 thousands of people were estimated to be diagnosed with parkinson's disease worldwide, 2.4 times higher than 1990, and there is a possibility of increasing environmental exposure (e.g., pesticides, solvents, metals) associated with industrialization. It is estimated that by 2020, about 93 ten thousand people in the united states will be diagnosed with parkinson's disease. With the advent of the aging society, the increasing population of the aging population has led to a significant rise in prevalence of parkinson's disease worldwide (particularly in china), and positive treatment of parkinsonism epidemics has contributed to positively address this challenge. At present, most of the clinical treatments for the parkinsonism use chemical medicaments based on dopamine, and have the defects of large side effect, influence on the treatment effect after long-term use, permanent damage to nerves and the like when serious, so that the search for medicaments with small side effect and good treatment effect is urgent. The natural medicine refers to a natural product with pharmacological activity naturally occurring in nature such as plants, animals, microorganisms and minerals, the natural medicine has the advantage of low toxicity, and plant and fruit extracts have been shown to have neuroprotective effects on neurodegenerative diseases. Natural compounds have strong antioxidant properties, which are usually associated with their neuroprotective effect against a variety of neurodegenerative diseases, and despite the wide variety of plants in the world, their anti-parkinsonism activity has been studied very limited, so future research into plants and their bioactive compounds is promising.
The root of false cimicifuga (a.sylvester kostel.) is called as Jinmao notoginseng in the shanxi area of china, which is one of the seven drugs of shanxi, is commonly used in the folk for treating injuries and strain muscle and bone pain, and has the effects of relaxing tendons and activating collaterals and relieving pain. At present, no research report on chemical components and biological activity of the false cimicifuga (A.sylvester Kostel.) exists at home and abroad, and the research on the activity of the false cimicifuga plants is mostly focused on ethanol extracts, so that the research shows that the ethanol extracts of the plants have certain effects in the aspects of antioxidation, blood sugar reduction, thrombus resistance, inflammation resistance, bacteria resistance and the like.
Disclosure of Invention
The application aims at providing a new application of dicaffeoyl glucose in pharmacy.
The application provides the use of a compound or a pharmaceutically acceptable salt or ester thereof in:
(1) Preparing a medicament for treating and/or preventing and/or relieving and/or improving parkinsonism;
(2) Preparing a medicament for treating and/or preventing and/or relieving and/or improving symptoms of an animal model of parkinsonism;
the structural formula of the compound (hereinafter also referred to as dicaffeoyl glucose) is shown in formula I:
alternatively, according to the above-mentioned use, the parkinson's disease is parkinson's disease caused by MPTP; the parkinsonism animal model is prepared by adopting MPTP. In the PD animal model, MPTP is converted into MPP+, MPP+ mainly causes dopaminergic neurodegeneration, and inhibits lipid peroxidation.
Alternatively, the animal is a mouse or zebra fish, according to the use described above.
The application also provides a preparation method of the compound, which comprises the following steps:
(1) Pulverizing rhizoma cimicifugae, soaking in 95% ethanol at room temperature for one week, extracting with 95% ethanol under reflux for 2 times and 60% ethanol under reflux for 1 time, extracting for 2 hr each time, and concentrating all ethanol extractive solutions until no ethanol smell exists to obtain extract;
(2) Suspending the extract obtained in the step (1) in water to obtain a suspension, sequentially extracting the suspension by using petroleum ether, ethyl acetate and n-butanol to obtain a petroleum ether extract, an ethyl acetate extract and an n-butanol extract;
(3) Subjecting the ethyl acetate extract obtained in the step (2) to a silica gel column, and performing gradient elution by using a dichloromethane-methanol elution system at a volume ratio of 100:0 to 0:100 to obtain fractions A1-A75;
(4) Subjecting the fraction A31-A40 obtained in the step (3) to a polyamide column, and performing gradient elution by using a methylene dichloride-methanol eluting system at a volume ratio of 100:0 to 0:100 to obtain a fraction B1-B59;
(5) And (3) loading the fraction B30 obtained in the step (4) on a Sephadex LH-20 gel column, and eluting with methanol to obtain yellow powder which is the compound in the claim 1.
The application also provides a product which contains the compound and is used as an active ingredient.
Optionally, according to the above product, the function of the product is any one of the following:
1) Treating and/or preventing and/or alleviating and/or ameliorating parkinson's disease;
2) Treating and/or preventing and/or alleviating and/or ameliorating cardiovascular diseases;
3) Treating and/or preventing and/or alleviating and/or ameliorating neurological disorders.
The application of the compound or the pharmaceutically acceptable salt or ester thereof in preparing the medicaments for treating and/or preventing and/or relieving and/or improving the cardiovascular diseases also belongs to the protection scope of the application.
The application of the compound or the pharmaceutically acceptable salt or ester thereof in preparing the medicament for treating and/or preventing and/or relieving and/or improving the neurological diseases also belongs to the protection scope of the application.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine; the carrier includes diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. which are conventional in the pharmaceutical field.
The medicine can be prepared into various forms such as injection, tablet, powder, granule, capsule, oral liquid, ointment, cream, etc.; the medicaments of the various formulations can be prepared according to the conventional method in the pharmaceutical field.
The above medicine can be introduced into organism such as muscle, intradermal, subcutaneous, intravenous, and mucosal tissue by injection, nasal drop, eye drop, permeation, absorption, physical or chemical mediation; or mixed or wrapped with other substances and introduced into the body.
Experiments prove that the dicaffeoyl glucose can treat the Parkinson disease of the zebra fish. Therefore, the dicaffeoyl glucose can be used for preparing medicines for treating parkinsonism, medicines for treating or preventing nervous diseases and other related fields, and provides a new medicine and treatment idea for treating or preventing parkinsonism.
Drawings
FIG. 1 is a structural formula of dicaffeoyl glucose.
Figure 2 is a graph showing that dicaffeoyl glucose promotes recovery of motion in zebra fish parkinson's disease.
Figure 3 is a graph showing that dicaffeoyl glucose promotes recovery of motion in zebra fish parkinson's disease.
Detailed Description
The following detailed description of the application is provided in connection with the accompanying drawings that are presented to illustrate the application and not to limit the scope thereof. The examples provided below are intended as guidelines for further modifications by one of ordinary skill in the art and are not to be construed as limiting the application in any way.
The experimental methods in the following examples, unless otherwise specified, are conventional methods, and are carried out according to techniques or conditions described in the literature in the field or according to the product specifications. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified. The quantitative tests in the following examples were all set up in triplicate and the results averaged.
The zebra fish used in the following examples were young zebra fish that were hatched for three days.
The model agent for Parkinson's disease MPTP used in the following examples was manufactured by Beyotime Biotechnology company under the trade name 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride as st1020-5 mg.
EXAMPLE 1 preparation of dicaffeoyl glucose
(1) Pulverizing rhizoma cimicifugae into fine pieces, and soaking in 95% ethanol at room temperature for one week. Then, the rhizoma cimicifugae root is extracted with 95% ethanol under reflux for 2 times, and 60% ethanol under reflux for 1 time, each for 2h. Concentrating all ethanol extractive solutions until no ethanol smell is present, to obtain extract.
(2) Suspending the extract obtained in the step (1) in water to obtain a suspension, and sequentially extracting the suspension with petroleum ether, ethyl acetate and n-butanol to obtain petroleum ether extract, ethyl acetate extract and n-butanol extract.
(3) Subjecting the ethyl acetate extract obtained in the step (2) to a silica gel column, and subjecting the ethyl acetate extract to gradient elution by using a methylene chloride-methanol elution system at a volume ratio of 100:0 to 0:100 to obtain 75 fractions (A1-A75).
(4) Subjecting fraction A31-A40 obtained in step (3) to a polyamide column, and subjecting to gradient elution with a methylene chloride-methanol elution system at a volume ratio of 100:0 to 0:100 to obtain 59 fractions (B1-B59).
(5) And (3) loading the fraction B30 obtained in the step (4) on a Sephadex LH-20 gel column, and eluting with methanol to obtain yellow powder.
And (5) identifying the yellow powder obtained in the step (5) by nuclear magnetism, mass spectrum and infrared. Specific data are as follows.
HR-ESI-MS：m/z 527.1162[M+Na] + (calculated value: 527.1160)
IR v max (KBr)：3287，1699，1605，1522，1272，1165cm -1 。
1 H NMR(600MHz，CD 3 OD): alpha-D-glucopyranose: delta 5.24 (1 h, d, j=3.5 hz, h-1), 3.75 (1 h, dd, j=9.8, 3.5hz, h-2), 5.54 (1 h, t-like, h-3), 5.10 (1 h, t-1ike, j=9, 8, 9-4), 4.13 (1 h, m, h-5), 3.57 (2 h, overlapped, h-6 "), 6.97 (2 h, overlapped, h-2', 2"), 6.72 (2 h, d, j=8.2 hz, h-5',5 "), 6.84 (2 h, overlapped, h-6', 6"), 7 (1 h, d, j=15.8 hz, h-7'), 7.48 (1 h, d, j=15.8 hz), and 6.8 hz (19, 9 h-8 hz, 8 h=15, 8 h-8 hz). beta-D-glucopyranose: δ4.70 (1H, d, j=7.7hz，H-1)，3.50(1H，t-1ike，J＝8.8，8.6Hz，H-2)，5.30(1H，t-like，J＝9.5，9.5Hz，H-3)，5.07(1H，t-like，J＝9.8，9.7Hz，H-4)，3.67(1H，m，H-5)，3.65(2H，overlapped，H-6)，6.97(2H，overlapped，H-2′，2″)，6.71(2H，d，J＝8.2Hz，H-5′，5″)，6.84(2H，overlapped，H-6′，6″)，7.47(1H，d，J＝15.8Hz，H-7′)，7.48(1H，d，J＝15.8Hz，H-7")，6.19(1H，d，J＝15.9Hz，H-8′)，6.14(1H，d，J＝15.8Hz，H-8″)。
13 C NMR(150MHz，CD 3 OD): alpha-D-glucopyranose: delta 93.9 (C-1), 72.0 (C-2), 74.6 (C-3), 70.7 (C-4), 71.0 (C-5), 62.2 (C-6), 127.8, 127.6 (C-1 ', C-1 "), 115.4, 115.4 (C-2', C-2"), 146.6, 146.6 (C-3 ', C-3 "), 149.7, 149.5 (C-4', C-4"), 116.7, 116.7 (C-5 ', C-5 "), 123.6, 123.4 (C-6', C-6"), 148.3 (C-7 '), 147.7 (C-7'), 114.9 (C-8 '), 114.2 (C-8 "), 169.2, 168.5 (C-9', C-9"). beta-D-glucopyranose: delta 98.3 (C-1), 74.6 (C-2), 70.7 (C-4), 75.8 (C-5), 62.3 (C-6), 127.7, 127.5 (C-1 ', C-1 "), 115.5, 115.4 (C-2', C-2"), 146.6 (C-3 ', C-3 "), 149.7, 149.6 (C-4', C-4"), 116.7, 116.7 (C-5 ', C-5 "), 123.6, 123.4 (C-6', C-6"), 148.4 (C-7 '), 147.8 (C-7'), 114.7 (C-8 '), 169.0, 168.4 (C-9', C-9 ").
The yellow powder is the 3, 4-di-O- (E) -caffeoyl-alpha/beta-D-glucopyranose (also called as dicaffeoyl glucose herein), and the structural formula is shown in figure 1.
Example 2, recovery test of Dicaffeoyl glucose in promoting movement ability of Zebra fish in Parkinson's disease
(1) Preparation of young zebra fish
Wild zebra fish are all from the China zebra fish resource center, and are maintained according to a standard scheme. The fish were maintained at 28.5℃under 14 hours light/10 hours dark conditions. Zebra fish embryos were obtained by natural mating, further washed and stored in medium E3 containing 2mg/L methylene blue (5 mM NaCl,0.17mM KCl, 0.33mM CaCl2, and 0.33mM MgSO4). The pH of the culture medium is maintained at 7.1 and changed every day until the young zebra fish is hatched.
(2) Experimental grouping and processing
a. Experimental group: the 3-day-old zebra fish larvae were randomly transferred to 24-well cell culture plates, 15 larvae per well, and the larvae were exposed to 0.05mg/ml MPTP solution until the zebra fish larvae developed to 4 days. And then the mixed solution containing MPTP and dicaffeoyl glucose with different concentrations is used for common treatment until the young fish develop to 6 days. In the mixed solution, the MPTP concentration was 0.05mg/ml, and the concentration of the dicaffeoyl glucose solution was 200 μm/L,500 μm/L and 1000 μm/L, respectively. The MPTP solution and the mixed solution were each prepared from an aqueous E3 solution (5mM NaCl,0.17mM KCl,0.4mM CaCl2 and 0.33mM MgSO4). Exposure of zebra fish larvae to these doses of dicaffeoyl glucose solution did not cause any significant side effects. The amount of MPTP solution or mixed solution per well was 1ml.
b. Blank control group: the zebra fish larvae developed for 3 days are randomly transferred to a 24-hole cell culture plate, 15 larvae per hole are exposed to E3 water solution until the larvae develop for 6 days. The amount of aqueous E3 solution used per well was 1ml.
c. Parkinson's disease model group: the treatment method is similar to the experimental group, and the difference is that: without treatment with dicaffeoyl glucose solution, the MPTP concentration per well of the 24-well plate was 0.05mg/ml and the volume was 1ml.
(3) Test method
In order to comprehensively and systematically test the improvement effect of dicaffeoyl glucose on the pd-like motion profile of the juvenile zebra fish, a behavioural method is adopted. Zebra fish larvae developed to 6 days were placed in 48-well plates with 1 well in 1000 μl of culture broth. After 20min adaptation with DanioVision (Noldus), the 1 hour movement test was recorded at 10min/10min light/dark cycle. And analyzing the total swimming distance, the swimming speed and the movement accumulation time of the juvenile fish.
Four independent experiments were performed, 10 sub-samples per repeat dose. Data are expressed as mean ± SEM, p < 0.05, p < 0.01, p < 0.001, and p < 0.0001.
(4) Results
The experimental results are shown in fig. 2 and 3, wherein the control group is a juvenile fish experimental result treated by a blank control group, the MTPT induced parkinsonism model group is a juvenile fish experimental result treated by a parkinsonism model group, the 200 mu m/L drug treatment group is a juvenile fish experimental result treated by MPTP and 200 mu m/L dicaffeoyl glucose, the 500 mu m/L drug treatment group is a juvenile fish experimental result treated by MPTP and 500 mu m/L dicaffeoyl glucose, and the 1000 mu m/L drug treatment group is a juvenile fish experimental result treated by MPTP and 1000 mu m/L dicaffeoyl glucose. FIG. 2 shows, from left to right, the total swimming distance, swimming speed and swimming time of the young zebra fish after MPTP co-treatment with 200 μm/L,500 μm/L and 1000 μm/dicaffeoyl glucose for 1 hour. Fig. 3 is a heat map of a record of 20 minutes of zebra fish larvae movement test and 1 hour of zebra fish larvae movement, in sequence from left to right.
The result shows that the motion ability of the zebra fish juvenile fish of the Parkinson's disease model group is obviously lower than that of the zebra fish juvenile fish of the negative control group, which indicates that the zebra fish Parkinson's disease model is successfully established, and the motion ability of the zebra fish juvenile fish with Parkinson's disease after being treated by dicaffeoyl glucose is obviously improved compared with that of the zebra fish juvenile fish of the Parkinson's disease model group.
The present application is described in detail above. It will be apparent to those skilled in the art that the present application can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the application and without undue experimentation. While the application has been described with respect to specific embodiments, it will be appreciated that the application may be further modified. In general, this application is intended to cover any variations, uses, or adaptations of the application following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the application pertains. The application of some of the basic features may be done in accordance with the scope of the claims that follow.
Claims (9)
1. Use of a compound or a pharmaceutically acceptable salt or ester thereof in the following:
(1) Preparing a medicament for treating and/or preventing and/or relieving and/or improving parkinsonism;
(2) Preparing a medicament for treating and/or preventing and/or relieving and/or improving symptoms of an animal model of parkinsonism;
the structural formula of the compound is shown as formula I:
2. the use according to claim 1, characterized in that:
the parkinsonism is parkinsonism caused by MPTP;
the parkinsonism animal model is prepared by adopting MPTP.
3. The use according to claim 1, characterized in that: the animals are mice or zebra fish.
4. A process for the preparation of a compound as claimed in claim 1 comprising the steps of:
(1) Pulverizing rhizoma cimicifugae, soaking in 95% ethanol at room temperature for one week, extracting with 95% ethanol under reflux for 2 times and 60% ethanol under reflux for 1 time, extracting for 2 hr each time, and concentrating all ethanol extractive solutions until no ethanol smell exists to obtain extract;
(2) Suspending the extract obtained in the step (1) in water to obtain a suspension, sequentially extracting the suspension by using petroleum ether, ethyl acetate and n-butanol to obtain a petroleum ether extract, an ethyl acetate extract and an n-butanol extract;
(3) Subjecting the ethyl acetate extract obtained in the step (2) to a silica gel column, and performing gradient elution by using a dichloromethane-methanol elution system at a volume ratio of 100:0 to 0:100 to obtain fractions A1-A75;
(4) Subjecting the fraction A31-A40 obtained in the step (3) to a polyamide column, and performing gradient elution by using a methylene dichloride-methanol eluting system at a volume ratio of 100:0 to 0:100 to obtain a fraction B1-B59;
(5) And (3) loading the fraction B30 obtained in the step (4) on a Sephadex LH-20 gel column, and eluting with methanol to obtain yellow powder which is the compound in the claim 1.
5. A product, characterized in that: comprising the compound according to claim 1 as active ingredient.
6. The product according to claim 5, wherein: the function of the product is any one of the following:
1) Treating and/or preventing and/or alleviating and/or ameliorating parkinson's disease;
2) Treating and/or preventing and/or alleviating and/or ameliorating cardiovascular diseases;
3) Treating and/or preventing and/or alleviating and/or ameliorating neurological disorders.
7. Use of a compound as claimed in claim 1 or a pharmaceutically acceptable salt or ester thereof for the manufacture of a medicament for the treatment and/or prophylaxis and/or alleviation and/or amelioration of cardiovascular disease.
8. Use of a compound as claimed in claim 1 or a pharmaceutically acceptable salt or ester thereof for the manufacture of a medicament for the treatment and/or prophylaxis and/or alleviation and/or amelioration of a neurological disorder.
9. A compound as claimed in claim 1.
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| CN202210627067.2A CN117159568A (en) | 2022-05-25 | 2022-05-25 | Application of dicaffeoyl glucose in preparation of medicines for treating and/or preventing and/or relieving and/or improving parkinsonism |
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| CN202210627067.2A CN117159568A (en) | 2022-05-25 | 2022-05-25 | Application of dicaffeoyl glucose in preparation of medicines for treating and/or preventing and/or relieving and/or improving parkinsonism |
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